Mouse experiments show treatment dampens overactive response to infection
Injections of an obscure cell best known for making collagen might quell the runaway inflammation that underlies lethal sepsis, a study in mice shows. Animals getting fibroblastic reticular cells were much more likely than others to survive sepsis, an immune overreaction typically triggered by bacterial infections reaching the blood.
Although the research is still at an early stage, the findings brighten prospects for finding an effective treatment for the condition. Sepsis is a medical emergency. Even with antibiotic treatment, a bacterial blood infection can flip the immune system into overdrive and flood the body with inflammatory cells and proteins, damaging organs. That makes sepsis fatal roughly 25 to 40 percent of the time, killing an estimated 7.3 million people worldwide every year. Options for treating sepsis are limited because suppressing immunity amid an infection is ill-advised.
Fibroblastic reticular cells, which build and maintain connective tissues such as collagen in lymph nodes and the spleen, also guide the actions of immune cells that inhabit these tissues. In the August 13 Science Translational Medicine, researchers report that injections of cultured reticular cells seem to keep the immune response in check in mice with sepsis. The cells do so by blocking inflammation and preserving needed immune cell populations in the spleen.
“I’m encouraged by these results,” says Ron Daniels, a critical care physician at the Heart of England NHS Foundation Trust, which operates three hospitals in and around Birmingham. “The concept of using a cell itself is a fairly novel one,” he says, noting that many previous attempts at fighting sepsis have relied on compounds.
In experiments, the researchers injected mice with a bacterial toxin or punctured the animals’ colons. Both caused bacterial infections leading to sepsis. Since sepsis in humans is 10 times as common in old people as in young, the researchers induced the condition in 16 older mice, age 18 to 24 months. Five of six mice getting the reticular cells four hours after infection survived, whereas only one of 10 control mice getting a saline injection did. The treatment was similarly effective in young mice when given four hours after infection.
The researchers also tested the experimental therapy on young mice 16 hours after an intestinal puncture. While all control mice died, four of nine receiving the reticular cells survived. Other tests showed the mice getting the cells retained more immune cells in their spleens.
The researchers found that fibroblastic reticular cells trigger the release of nitric oxide using an enzyme called nitric oxide synthase-2. In a separate experiment, reticular cells from mice lacking the enzyme failed to protect mice from sepsis. Mice getting normal reticular cells not only fared better but had lower levels of trouble-making inflammatory proteins called cytokines, says study coauthor Biju Parekkadan, a bioengineer at Harvard Medical School in Boston. Indeed, the reticular cells seem to defuse the “cytokine storm” that shows up in the blood in severe sepsis, the authors say.
“This was a really remarkable dampening” of the cytokine levels, Parekkadan says. The researchers hope to test the cells in larger mammals, perhaps sheep or pigs, or possibly in patients so gravely ill with sepsis that they have little to lose.
A “blue-sky idea” for cellular treatment, says Daniels, who wasn’t part of this study, would be to use it to rescue people in the throes of advanced sepsis. Meanwhile, he says, it would be worthwhile to test the concentrations of fibroblastic reticular cells in people who have survived or succumbed to sepsis to clarify the cells’ natural role in the condition.
Editor's note: This story was updated August 29, 2014, to correct the age of the older mice in the experiment. The mice were age 18 to 24 months, not 16 to 24 months.
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